Antidepressant Effects Research Articles

Long-Term Effects of Single and Repeated Ketamine Infusions on Treatment-Resistant Depression: A Retrospective Chart Review Study

Treatment-resistant depression (TRD) is a substantial public health burden with limited treatment options. Recent evidence suggests that single and repeated-dose ketamine infusions have rapid and significant antidepressant effects on individuals with TRD. Few studies have compared single or repeated (6) ketamine infusions past 14 days post-treatment. This retrospective chart review study investigated the long-term effects of single (n = 9) and repeated (6) (n = 5) high-dose (1 mg/kg) intravenous ketamine infusions on TRD 30 days post-infusion(s) (N = 14). Changes in depressive symptoms were measured by comparing Beck Depression Inventory (BDI-II) scores pre- and 30 days post-treatment for an understanding of long-term efficacy in clinical practice. Results indicated that ketamine has the potential to be an effective and enduring intervention for TRD, adding treatment and management options that are currently limited.

Empagliflozin ameliorates olfactory bulbectomy-induced depression by mitigating oxidative stress and possible involvement of brain derived neurotrophic factor in diabetic rats

Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, has recently reported to prevent the depression as chronic animal model. However, its impact on neuroinflammation-mediated depression were remains unexplored. The present study aimed to explore the antidepressant potential of empagliflozin using a neuroinflammation-mediated depression involving the olfactory bulbectomy (OBX) model in rats. To establish this model, initially a low dose of streptozotocin was injected to induce diabetes in all group of animals. Following the confirmation of hyperglycemia, OBX surgery was performed. Post-surgery, the drug treatments were administered orally for 14 consecutive days. The study evaluated the effects of daily oral administration of empagliflozin at doses of 5 and 10 mg/kg, alongside metformin (200 mg/kg) and clomipramine (50 mg/kg), on OBX-induced behavioral depression in rats. Separate sham and vehicle control groups were also maintained. Behavioral parameters in open field, forced swim test, elevated plus maze and splash test were recorded on 28th day. Results showed that empagliflozin, particularly at the higher at the higher dose, significantly enhanced behavioral outcomes, evidenced by increased distance traveled, greater open arm entries, and reduced immobility, alongside a notable reduction in grooming time. Moreover, empagliflozin significantly restored the antioxidants level specifically Glutathione (GSH) and Catalase (CAT) in OBX insulted rat brain and reversed Lipid peroxidase (LPO). Notably, molecular docking study demonstrated a good binding affinity of empagliflozin for Brain-Derived Neurotrophic Factor (BDNF), suggesting that its antidepressant effects may be mediated through the modulation of the BDNF pathway. These findings support the potential therapeutic application of empagliflozin for depression, particularly in cases associated with neuroinflammation and oxidative stress.

Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.

Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.

Morphological correlates of anxiety-related experiences during a ketamine infusion

Objectives: Ketamine exerts rapid antidepressant effects by enhancing neuroplasticity, particularly in the amygdala and hippocampus—regions involved in fear processing and learning. While the role of ketamine’s dissociative effects in its antidepressant response is debated, anxiety experienced during infusion has been negatively correlated with treatment outcomes. Methods: In this single-blind, placebo-controlled study, a subset of 17 healthy volunteers (6 males, 23.12 ± 1.9 years) received intravenously a placebo in the first and 0.5 mg/kg racemic ketamine in the second session. Anxiety-related experiences were assessed by the 5D-ASC score obtained post-infusion, structural magnetic resonance imaging scans were acquired 4 h post-infusion. An anxiety-score was obtained from the 5D-ASC. Relation between post-placebo amygdala volume, hippocampal volume, and its subfields with the anxiety-score were assessed using linear regression models. Results: Results showed a statistically significant negative relation between hippocampal head volume and the anxiety score (β = −0.733, p = 0.006), with trending negative association for each subfield’s head and the score. Conclusion: These findings suggest that anxiety-related experiences during ketamine infusion may be mediated by the hippocampus, with smaller hippocampal volumes leading to more anxiety-related experiences. Thus, hippocampal subfield volumes may be used as a predictor for anxiety-related events during ketamine use and might predict treatment outcome in future approaches.

Amino acid metabolites profiling in unpredictable chronic mild stress-induced depressive rats and the protective effects of Gastrodia elata Blume and gastrodin

Ethnopharmacological relevanceMajor depressive disorder (MDD) is a prevalent condition that affects approximately 350 million people worldwide. Several studies have identified changes in amino acids in the blood of MDD patients, suggesting their potential as biomarkers to better understand their role in depression. Gastrodia elata Blume (GEB) and its active compound gastrodin (GAS) are recognized for their antidepressant properties. However, their effects on amino acid profiles and their potential role in alleviating depression remain poorly understood. Understanding how GEB and GAS influence amino acid metabolism may offer novel insights into their mechanisms in alleviating depression, potentially leading to more targeted therapeutic strategies. Aim of the studyThis study aimed to investigate the potential role of supplementing GEB and its active compound GAS to reverse altered amino acid profiles in depressed rats. Materials and methodsTo achieve this, six-week-old SD rats were induced depressive-like behaviors by the UCMS rat model for 5 weeks. Groups receiving GEB or GAS were administered orally via gavage daily within the UCMS model. Serum samples were collected and analyzed using a targeted metabolomics approach employing LC-MS for amino acid profiling. ResultsA total of 38 amino acid metabolites were identified, 17 of which were significantly altered following UCMS. UCMS rats exhibited perturbed arginine biosynthesis, arginine and proline metabolism pathways. Changes in key amino acids in these metabolic pathways were reversed following supplementation with GEB and GAS, which also alleviated depressive symptoms. ConclusionsIn conclusion, UCMS-induced depression in rats causes changes in some amino acid metabolites similar to those found in human depression, validating its relevance as a model for studying depression. Additionally, the research suggests that GEB and GAS may exert antidepressant effects by regulating amino acid metabolism.

Integrated network pharmacology and transcriptomics to reveal the mechanism of Passiflora against depressive disorder: An observational study.

Relevant studies have pointed out that Passiflora could relieve depressive disorder (DD) related symptoms, such as anxiety and insomnia, but its mechanism in DD has not been reported. In this study, DD-related transcriptome data was extracted from the Gene Expression Omnibus (GEO) database. Subsequently, 50 differentially expressed genes (DEGs) were screened by "limma," and the enrichment analysis of these DEGs revealed that they were associated with neuro-inflammatory-related signaling pathways, including IL-17, TNF, NF-kappa B, etc signaling pathways. Then, CCDC58, CXCL5, EGR1, LOC101929855, SCML1, and THBS1 were screened as biomarkers of DD by the least absolute shrinkage and selection operator (LASSO) analysis. Moreover, Harmaline, Harmine, Quercetin, and Kaempferol were the key chemically active ingredients of Passiflora. Noticeable, THBS1 and Quercetin were connected closely. In addition, the quantitative real-time polymerase chain reaction (qRT-PCR) confirmed that the key biomarkers (EGR1 and THBS1) were significantly lowly expressed in DD samples. In summary, we identified 2 key biomarkers of DD and 4 key chemically active ingredients of Passiflora. The potential mechanism of antidepressant effect of DD associated with neuro-inflammatory responses and neurotransmitter function. These might related to the synergistic activity of its key active ingredients with TNF-α, IL-1β, IL-6, etc, which work with EGR1 and THBS1 to regulate IL-17, NF-kappa B, TNF, etc signaling pathways. These findings might help to deepen the understanding of the mechanism of Passiflora in clinical treatment of DD.

The Role of BDNF in the Antidepressant Effects of Electroconvulsive Therapy.

Electroconvulsive therapy (ECT) is an effective treatment method for depression therapy. It produces a number of biological effects, including neurotrophic factors regulation. In the present paper, we investigated the ECT response in depressed rats subjected to the variable frequency ultrasound (20-45 kHz) and examined the contribution of brain-derived neurotrophic factor (BDNF) expression changes to the observed effects. The obtained results reflect the therapeutic potential of ECT for the treatment of depressive-like state in rodents and indicate the role of BDNF in these processes. In future research, it is necessary to investigate the relationship between neurotrophin and structural changes and to study other neurotrophic biomarkers that may be associated with the development of depression-like state and the therapy response.

The antidepressant effect of Komagataella pastoris KM 71 H in maternal separation mice model mediated by the microbiota-gut-brain axis

BackgroundThe intestinal microbiota plays a fundamental role in maintaining host health, especially during childhood, a critical period for its establishment. Early life stress can lead to shifts in gut microbiota composition, thus increasing the risk of major depressive disorder (MDD) in adulthood. The supplementation with probiotics restores intestinal permeability and the health of gut microbial communities, therefore being potential study targets for the treatment of MDD. In this sense, the yeast Komagataella pastoris was reported as a promising probiotic with antidepressant effect. MethodsHence, the present study aims to investigate this effect in mice submitted to maternal separation (MS) 3 h per day from PND2 to PND14. Adult mice and mothers were treated with K. pastoris KM71H (8 log UFC.g−1/per animal, i.g.) or PBS (500 µl, i.g.) for 14 days. After behavioral tests, the animals were euthanized, followed by hippocampi and intestines removal for biochemical analysis. ResultsOn behavioral tests, K. pastoris KM71H treatment reduced the immobility time in TST of adult mice and increased the grooming activity in splash test of adult mice and mothers induced by MS. The probiotic treatment restored plasma corticosterone levels and glucocorticoid receptor expression in hippocampi, alongside nitrate/nitrite levels and superoxide dismutase activity in intestine, in addition to reducing reactive species levels in both structures. Moreover, it also normalized the fecal pH and water content of feces. ConclusionThus, we conclude that K. pastoris KM71H is a promising therapeutic strategy for the treatment of MDD.

Effects of an acute maximal exercise bout on serum insulin-like growth factor-1 in adults with MDD

Exercise has acute, positive effects on mood and can lead to antidepressant effects over time when repeated regularly. The mechanisms underlying the antidepressant effects of exercise training are not well known, limiting the prescription of exercise training for depression. Serum Insulin-Like Growth Factor-1 (IGF-1) appears dysregulated in those with Major Depressive Disorder (MDD), suggesting MDD could inhibit or alter the IGF-1 response to exercise. In healthy individuals, exercise has been shown to acutely increase serum IGF-1, which may act positively on the dysregulated IGF-1 system in MDD. Therefore, the purpose of this study was to examine the sensitivity of serum IGF-1 levels to an acute maximal exercise bout in adults with MDD and healthy controls. Additionally, clinical and behavioral factors of MDD are likely to affect this system, such as depression severity, antidepressant usage and physical activity habits. Baseline data were used from a larger trial in Germany (SPeED Study) collected from individuals with mild to moderate MDD (n=113) and healthy controls (n=34) that were matched for age, sex, and education. Demographics, depression severity (Hamilton Depression Rating Scale-17), self-reported antidepressant usage, MVPA (International Physical Activity Questionnaire-Short Form), and blood draws before and after a maximal exercise test were collected. Multiple linear regressions were conducted to determine relationships between depression severity, antidepressant usage, and physical activity with peripheral IGF-1 levels following acute exercise. Covariates included demographic factors and IGF-1 pre-exercise (baseline levels). Acute IGF-1 changes occurred similarly in depression (mean ± SD; 11.3 ± 12.9) as well as healthy adults (11.3 ± 20.4: p>0.05). Neither depression severity, antidepressant use, nor regular physical activity were significant predictors of peripheral IGF-1 levels at baseline or following exercise. Individuals with MDD are likely to have favorable exercise-induced IGF-1 changes regardless of clinical and behavioral differences. Acute exercise increases peripheral IGF-1 briefly, and in response to repeated exercise bouts, the IGF-1 system could normalize over time. The normalization of the IGF-1 system might be a possible mechanism underlying mood increases that occur during exercise with exercise training research warranted.

Identification of molecular targets of Hypericumperforatum in blood for major depressive disorder: a machine-learning pharmacological study

BackgroundMajor depressive disorder (MDD) is one of the most common psychiatric disorders worldwide. Hypericumperforatum (HP) is a traditional herb that has been shown to have antidepressant effects, but its mechanism is unclear. This study aims to identify the molecular targets of HP for the treatment of MDD.MethodsWe performed differential analysis and weighted gene co-expression network analysis (WGCNA) with blood mRNA expression cohort of MDD and healthy control to identify DEGs and significant module genes (gene list 1). Three databases, CTD, DisGeNET, and GeneCards, were used to retrieve MDD-related gene intersections to obtain MDD-predicted targets (gene list 2). The validated targets were retrieved from the TCMSP database (gene list 3). Based on these three gene lists, 13 key pathways were identified. The PPI network was constructed by extracting the intersection of genes and HP-validated targets on all key pathways. Key therapeutic targets were obtained using MCODE and machine learning (LASSO, SVM-RFE). Clinical diagnostic assessments (Nomogram, Correlation, Intergroup expression), and gene set enrichment analysis (GSEA) were performed for the key targets. In addition, immune cell analysis was performed on the blood mRNA expression cohort of MDD to explore the association between the key targets and immune cells. Finally, molecular docking prediction was performed for the targets of HP active ingredients on MDD.ResultsDifferential expression analysis and WGCNA module analysis yielded 933 potential targets for MDD. Three disease databases were intersected with 982 MDD-predicted targets. The TCMSP retrieved 275 valid targets for HP. Separate enrichment analysis intersected 13 key pathways. Five key targets (AKT1, MAPK1, MYC, EGF, HSP90AA1) were finally screened based on all enriched genes and HP valid targets. Combined with the signaling pathway and immune cell analysis suggested the effect of peripheral immunity on MDD and the important role of neutrophils in immune inflammation. Finally, the binding of HP active ingredients (quercetin, kaempferol, and luteolin) and all 5 key targets were predicted based on molecular docking.ConclusionsThe active constituents of Hypericumperforatum can act on MDD and key targets and pathways of this action were identified.

Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms.

Research over the past years has compared the enantiomers (S)-ketamine (esketamine) and (R)-ketamine (arketamine) of the previously known racemic mixture called ketamine (R/S-ketamine). Esketamine has been found to be more potent, offering three times stronger analgesic effects and 1.5 times greater anesthetic efficacy than arketamine. It provides smoother anesthesia with fewer side effects and is widely used in clinical settings due to its neuroprotective, bronchodilatory, and antiepileptic properties. Approved by the FDA and EMA in 2019, esketamine is currently used alongside SSRIs or SNRIs for treatment-resistant depression (TRD). On the other hand, arketamine has shown potential for treating neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis, offering possible antidepressant effects and anti-inflammatory benefits. While esketamine is already in clinical use, arketamine's future depends on further research to address its safety, efficacy, and optimal dosing. Both enantiomers hold significant clinical value, with esketamine excelling in anesthesia, and arketamine showing promise in neurological and psychiatric treatments.

An Assessment of Antidepressant Activity of Etlingera elatior Alone and in Combination with Fluoxetine

Aim: Present study deals to access the antidepressant activity of Etlingera elatior leaves extract in rodent. Background: Etlingera elatior is a species of herbaceous perennial plant in the family Zingiberaceae; native to Indonesia, Thailand, Malaysia and New Guinea. Depression is one of the most common mental disorders affecting humans, pathological basis of which is not fully understood. The current antidepressant drugs have several adverse effects including their effects on cognition. Therefore, natural product are being evaluated for their antidepressant activities. Objective: In this study, Etlingera elatior leaf extracts are being evaluated for antidepressant activity in rodent models. A wide range of synthetic medicines that can be used to treat depression which may exerts various side effects such as dry mouth, gastrointestinal problems, nausea, respiratory problems, cardiac arrhythmias, drowsiness, anxiety etc. Hence, it becomes essential to discover new anti-depressant drug with more potency, efficacy and safety profile than those of marketed synthetic drugs. Methods: Using the forced swimming test, the tail suspension test, mouse 5-HTP-induced head twitches and estimation of brain lipid peroxidation modelsthe antidepressant efficacy of Etlingera elatior ethanolic extract was examined. Imipramine was used as reference standards. result: According to our study, Etlingera elatior significantly (p0.01) reduced immobility in tail suspension, forced swimming, and 5-HTP-induced head twitches in mice with depression that were comparable to imipramine. Results: According to our study, Etlingera elatior significantly (p 0.01) reduced immobility in tail suspension, forced swimming, and 5-HTP-induced head twitches in mice with depression that were comparable to imipramine. Conclusion: Based on the results obtained we can conclude that Etlingera elatior leaves extract possess significant antidepressant activity. The antidepressant effectiveness of Etlingera elatior leaves extract can be confirmed in the future by adding more models, and attempts can also be made to isolate and characterise the phytoconstituents responsible for the pharmacological action.

Research Progress on NMDA Receptor Enhancement Drugs for the Treatment of Depressive Disorder.

Major depressive disorder (MDD) is a severe mental illness with a complex etiology. Currently, many medications employed in clinical treatment exhibit limitations such as delayed onset of action and a high incidence of adverse reactions. Therefore, there is a pressing need to develop antidepressants that exhibit enhanced efficacy and safety. The N-methyl-D-aspartate receptor (NMDAR), a distinctive glutamate-gated ion channel receptor, has been implicated in the onset and progression of depressive disorder, as evidenced by both preclinical and clinical research. The NMDAR antagonist, ketamine, exhibits rapid and sustained antidepressant effects, holding promise as a novel therapeutic approach for depressive disorder. However, its psychotomimetic impact and potential for addiction have restricted its widespread clinical application. Notably, over the past decade, studies have suggested that enhancing NMDAR functionality can produce antidepressant effects with improved safety, especially with the emergence of NMDAR-positive allosteric modulators (PAMs). We view this as a potential novel strategy for treating depression, forming the basis for the narrative review that follows.

Evaluation of akathisia in patients receiving selective serotonin reuptake inhibitors/serotonin and noradrenaline reuptake inhibitors.

Akathisia is an underestimated but disturbing extrapyramidal side effect of antidepressants, which could reduce treatment compliance in mood disorders. This study aimed to investigate the frequency and risk factors in patients treated with selective serotonin reuptake inhibitors/serotonin and noradrenaline reuptake inhibitors (SSRI/SNRI). In addition, we assessed the impact of akathisia on the quality of life (QoL). Patients were aged between 18 and 75 years, receiving an SSRI/SNRI for 4-8 weeks, and were diagnosed with anxiety, depression, or obsessive-compulsive disorder. The Barnes Akathisia Rating Scale was used to assess the severity of the akathisia. QoL was evaluated using the Short Form 36 (SF-36) questionnaire. Akathisia was observed in 25% (50/198) of patients. Smokers and younger patients were more frequent among patients with akathisia. Physical functioning, physical role, vitality, and mental health domains of the SF-36 were reduced in the presence of akathisia. In conclusion, our results suggest that akathisia is not a rare side effect of SSRI/SNRI in patients with mood disorders, especially in smokers and younger patients. In addition, akathisia may reduce treatment compliance owing to a reduction in QoL. Further investigations are needed to confirm the risk factors, frequency, and consequences of treatment compliance for SSRI/SNRI-induced akathisia in patients with mood disorders.

7227 Acute Hyponatremia Following Initiation of Antidepressant in Patient on Desmopressin Treatment for AVP Deficiency

Abstract Disclosure: M.E. Horowitz: None. Y. Gao: None. S.B. Abraham: None. P. Kishore: None. Introduction: Intranasal desmopressin (DDAVP) is indicated as antidiuretic replacement therapy in arginine vasopressin (AVP) deficiency. It increases water permeability in the distal nephron, reducing urine output, increasing urine osmolality, and decreasing serum osmolality. Treatment is titrated to normalize serum sodium and urine output (UOP). Initiation of medications affecting sodium balance or fluid status may lead to abnormalities in these markers. One of these is escitalopram, an antidepressant which can cause hyponatremia attributed to inappropriate AVP secretion. We report a case of acute hyponatremia in a patient with previously stable sodium on chronic DDAVP who was started on escitalopram. Clinical Case: A 44-year-old female with history of a craniopharyngioma resection in 2007 complicated by AVP deficiency on chronic DDAVP, bipolar disorder, and depression presented with nausea, vomiting, and dizziness for two days. Patient was found to be hyponatremic to 118 mEq/L (135-145 mEq/L). Sodium checked one month prior was 135 mEq/L, and historically was never less than 130 mEq/L since 2008. DDAVP was prescribed since resection with few dose changes, at this time four 10mcg sprays in each nostril three times daily since 2020. Escitalopram 5mg daily was initiated two months prior. Desmopressin was held in the setting of hyponatremia, which resolved appropriately to 135 mEq/L over the first five days. During this time, the patient complained of large volume diuresis at ∼three liters daily. On day six, sodium acutely increased to 146 mEq/L; subcutaneous (SC) DDAVP was given and sodium normalized. UOP decreased significantly over the next 24 hours, but large volume diuresis resumed thereafter. On day 10, DDAVP SC was given, again decreasing UOP for 24 hours. Psychiatry recommended continuing escitalopram given improvement in psychiatric symptoms since initiation. Upon discharge, the patient was prescribed DDAVP two 10mcg sprays in each nostril nightly, a significant reduction compared to her prior dose. Sodium rechecked one week later remained within normal limits. Clinical Lessons: This effect of combination DDAVP and escitalopram has not been reported previously. Prescribers should be aware of the potential for hyponatremia and the need to adjust DDAVP dose in combined use. To avoid these risks in patients on chronic DDAVP, the side effects of antidepressants and antipsychotics should be reviewed prior to initiation. Presentation: 6/2/2024

Antidepressants account for the causal effect of major depressive disorder on type 2 diabetes

BackgroundPatients with major depressive disorder (MDD) face an elevated risk of type 2 diabetes (T2D). However, the contribution of the disease itself versus the side effects of antidepressants to this increased risk remains unclear. ObjectiveThis study aimed to investigate the overall and independent effects of MDD and exposure to antidepressants on T2D risk. MethodsSummary genome-wide association study datasets were utilized for the Mendelian randomization (MR) and multivariable MR (MVMR) analyses, including ones for MDD (N = 500,199), antidepressants (N = 175,161), and T2D (N = 933,970). Bayesian colocalization analysis was used to reveal shared genetic variation between MDD, antidepressants, and T2D. ResultsWe found that both MDD (OR: 1.15, CI: 1.03–1.30, P = 0.016) and antidepressants (OR: 1.37, CI: 1.22–1.53, P = 2.75E-08) have overall causal effects on T2D. While T2D was associated with the risk of antidepressant use (OR: 1.08, CI: 1.06–1.11, P = 8.80E-10), but not with the risk of MDD (OR: 1.00, CI: 0.98–1.01, P = 0.661). Our MVMR analysis showed that the use of antidepressants is associated with higher risks of T2D (OR: 1.21, CI: 1.07–1.37, P = 7.19E-04), while MDD is not linked to the risk of T2D (OR: 1.01, CI: 0.86–1.18, P = 0.799). Colocalization analysis identified two shared genetic loci between antidepressants and T2D. ConclusionsThe elevated T2D risk in MDD patients is chiefly caused by antidepressant use. These findings emphasize the importance of considering the impact of antidepressants on metabolic health in individuals with MDD.

12218 Gnrh Pulse Frequency And Irregularity Play A Role In Depression

Abstract Disclosure: J. Choi: None. M. Kim: None. Gonadotropin-releasing hormone (GnRH) has a role in hypothalamic control of depression, but the underlying patterns and relationship with downstream reproductive hormones are still unclear. Here we report that hypothalamic GnRH pulse frequency and irregularity increase before GnRH pulse amplitude slowly decreases during social defeated stress models (SDS). While mice castrated and testosterone inhibited induced depression by conducting SDS, these mice led to anti-depression effects and affected by GnRH signaling, indicating that high-frequency GnRH pulses. Regramming the endogenous GnRH pulses of depressed male mice via an optogenetic approach revealed that increasing GnRH pulses frequency causes depression acceleration, while lowering the frequency of and stabilizing GnRH pulses can slow down depression. In conclusion, GnRH pulses are important for depression in male mice. Presentation: 6/1/2024

Role of SIRT1-mediated synaptic plasticity and neurogenesis: Sex-differences in antidepressant-like efficacy of catalpol

BackgroundCatalpol, an important compound found in Rehmannia glutinosa (a plant with high nutritional and antidepressant medicinal value), exhibits various biological activities and has the ability to penetrate the blood-brain barrier. Our recent studies revealed a gender difference in the antidepressant activity of Rehmannia glutinosa with females showing better responses than males. Catalpol is likely the key compound responsible for this gender-specific difference, which caters to current clinical observations that the severity and impact of depression are approximately two to three times higher in females than in males. However, the sex-specific mechanism of catalpol's antidepressant effects remains unclear. Purpose and MethodsOur recent molecular network predictions suggest that the gender-specific antidepressant properties of catalpol primarily involve the regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Building on this, the present study used a well-established chronic unpredictable mild stress model of depression in mice to confirm the sex-specific antidepressant characteristics of catalpol over time and intensity. Furthermore, using SIRT1 inhibitors and activators, behavioral tests, hematoxylin & eosin, Nissl, and Golgi staining, western blotting, immunofluorescence, and real-time PCR, we evaluated the key indicators of depressive behavior, synaptic plasticity, and neurogenesis before and after SIRT1 intervention to comprehensively assess whether the sex-specific antidepressant mechanism of catalpol indeed involves SIRT1-mediated synaptic plasticity and neurogenesis. ResultsThe gender-dependent antidepressant effects of catalpol are characterized by a faster onset and stronger effects in females compared to males, with females showing stronger regulation of SIRT1-mediated synaptic plasticity and neurogenesis. Activation of SIRT1 preserved the gender differences in catalpol's effects on depressive behavior, hippocampal synaptic plasticity (including neuronal consolidation, neuronal density, dendritic spines, and PSD95 and SYP gene and protein expression), and neurogenesis (including enhancement of GAP43 and MAP2 expression, activation of c-myc, cyclinD1, Ngn2, and NeuroD1 mRNA levels, and upregulation of the Wnt3a/β-catenin/GSK-3β pathway), while inhibition of SIRT1 abolished these gender differences in the effects of catalpol. ConclusionsCatalpol exhibits higher antidepressant activity in female mice compared to male mice, and the mechanism underlying this gender difference in antidepressant effects may depend on catalpol's higher sensitivity in improving hippocampal SIRT1-mediated synaptic plasticity and neurogenesis in females. The novelty of this study lies in its first-time revelation of the gender-specific phenotypes, targets, and molecular mechanisms of the antidepressant effects of catalpol.

Rapid and Prolonged Antidepressant and Antianxiety Effects of Psychedelics and 3,4-Methylenedioxy-methamphetamine—A Systematic Review and Meta-Analysis

Rapid and Prolonged Antidepressant and Antianxiety Effects of Psychedelics and 3,4-Methylenedioxy-methamphetamine—A Systematic Review and Meta-Analysis

Not all types of depressed patients who persist with their antidepressant treatment improve in side effect complaints: A comparison of treatment completers and dropouts in the STAR*D trial.

There is a "traditional belief" that antidepressant side effect complaints improve with medication persistence; however, support for this theory has remained inconclusive. We aimed to examine if side effect complaints improved over time by modeling the relationship between side effect complaints and time at dropout for patients receiving citalopram during the first level of acute treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. We categorized the 2833 patients into five patterns by week of dropout. We used pattern-mixture modeling to model change in side effect complaints (frequency, intensity, and burden) over the 12-week course of treatment, while accounting for attrition and depressive severity. Using post-hoc linear contrasts, we compared the attrition patterns with the completers' pattern for severity of side effect complaints at each respective last visit prior to dropout as well as averaged side effect complaints across the duration of treatment. We also reported frequencies and tolerability of side effects for nine organ/function systems over the course of treatment. Patients who dropped out early exhibited worsening side effect burden and patients who dropped out later showed improvements in side effect frequency and intensity. Treatment completers improved in all side effect complaints over the course of treatment. Early attrition patterns had more severe side effect complaints for both tests of post-hoc linear contrasts than later attrition patterns and completers. Side effect complaints from antidepressant treatment improve over time, but only for some types of patients. As a precaution for early dropout, clinicians should monitor patients who exhibit worsening and more severe side effect complaints-especially in the first 6 weeks of antidepressant treatment. In addition, clinicians may want to consider changing the type of treatment early on for these patients, rather than encouraging them to persist with their current medication.